The Next Generation of Antigen-Specific T cells for Sarcoma Therapies for Sarcoma

Outcomes remain poor for patients with metastatic Synovial Sarcoma (SS) and Myxoid/ round cell liposarcoma (MRCL). Immunotherapeutic approaches may be well suited to SS and MRCL because both of these sarcoma subtypes characteristically express high levels of cancer testis antigens (CT Antigens). These immunogenic proteins are typically seen in some cancers and the germ cells of testis, but not other adult tissues. Several CT Antigens, including NY-ESO-1, are strongly expressed by both SS and MRCL. We have developed a methodology to make antigen specific T cells from the peripheral blood of patients that can target NY-ESO-1 and other CT antigens;…  Read More »

Pre-clinical development of anti-KIT CAR-Ts for metastatic GIST

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract affecting approximately 5,000 individuals in the US each year. Up to 90% of GISTs arise from the interstitial cells of Cajal (ICC) of the stomach or small intestine via mutations in the KIT receptor causing constitutive oncogenic signaling. In many cases, patients with unresectable KIT+ GIST develop liver metastases (LM) and harbor additional mutations in KIT which confer resistance to treatment with tyrosine kinase inhibitors (TKIs) imatinib and sunitinib. To address this unmet clinical need, our team previously developed human anti-KIT chimeric antigen receptor T cells…  Read More »

Adoptive cellular therapy for Ewing’s sarcoma

Tumor immunotherapy with chimeric antigen receptor (CAR)-modified T cells has shown substantial efficacy in early phase clinical trials. Targeting a single tumor associated antigen (TAA) could however result in creation of antigen escape variants. We have shown that simultaneous targeting of two TAAs with bispecific T-cell products can offset this antigen escape mechanism. To render T cells bispecific using a single molecule, we used systematic computational modeling to rationally design and construct a novel proof-of-principle bispecific CAR molecule that incorporates two scFv antigen-recognition domains, in tandem (TanCAR). Our data demonstrated that TanCAR-grafted T cells distinctly and specifically recognized and killed…  Read More »

Improving T-cell Therapy for Osteosarcoma

The long-term goal of this project is to develop an effective immunotherapy for patients with metastatic and/or recurrent OS osteosarcoma (OS), whose prognosis remains poor despite aggressive multimodality therapy. Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells has the potential to improve outcomes for patients with OS since CAR T-cell killing does not rely on the cytotoxic mechanism of conventional therapies. While CAR T cells have shown promise for the immunotherapy of B-cell malignancies in early phase clinical studies, T-cell therapy for solid tumors such as OS faces formidable challenges. For example, antitumor activity of T cells relies on significant…  Read More »

Epigenetic Mechanisms underlying Ewing Sarcoma Pathogenesis

  Rationale: Ewing sarcoma, the second most common pediatric bone cancer, is a highly lethal malignancy. Despite multimodal therapy, recurrence and mortality remain high for metastatic cases. It has been proposed that its refractory nature arises in part from resistance of a cancer stem cell (CSC) subpopulation to chemotherapy. Thus, it is essential that novel therapeutics target this population. We have found that the epigenetic modifier drug, JQ1, is highly toxic to Ewing sarcoma cells in vitro, and is especially efficacious in targeting the CSC subpopulation. Pilot studies further suggest that JQ1 attenuates tumorigenesis of xenografted Ewing sarcoma cells. JQ1…  Read More »

Identification of Causative Genetic Networks in Angiosarcoma

Malignant vascular tumors are a type of sarcoma that originates from transformed endothelial cells. While the disease is rare (2% of all sarcomas), these tumors are highly invasive and display low survival (50% lethality / year). Unlike the vast majority of cancers, the identification of causative genes in angiosarcoma is lagging behind other tumor types and therefore, advancements in early diagnostic markers, generation of animal models for the disease and development of therapeutic approaches has been severely impaired. An additional emerging concern has been the raising incidence of angiosarcoma in patients exposed to radiotherapy for breast cancer treatment. In this…  Read More »

Targeting Angiosarcoma Vascular and Metabolic Signaling by Blocking Beta Adrenergic Receptor Signaling

Angiosarcomas are highly lethal tumors composed primarily of aberrant lymphatic and/or vascular endothelial cells. These tumors most commonly occur as facial dermatologic lesions and account for over 50% of radiation-induced sarcomas following breast cancer therapy. The five year survival rate of angiosarcoma patients is less than 30%, and even the addition of novel molecularly-targeting therapies has shown a minimal to absent response. Very little therapeutic progress has been made over the past several decades to improve treatment outcomes, thus effective therapeutics against this disease are desperately needed. Preliminary data from our lab indicate that blocking beta adrenergic receptor (ADRB) signaling…  Read More »

Therapeutically Targeting the Hippo Pathway in Osteosarcoma

Osteosarcoma is a malignant bone cancer that predominantly affects young adults and children. Current treatments include pre-operative chemotherapy, followed by surgical removal of the tumor or amputation, and post-operative chemotherapy. However, despite several decades of study, a significant fraction of patients are refractory to these treatments and overall survival rates remain at only ~60%. Clearly, new therapeutic strategies to combat osteosarcoma need to be defined. One characteristic of osteosarcoma tumor cells that distinguishes them from normal cells is that they frequently harbor twice the normal number of chromosomes and are considered near tetraploid. Tetraploidy is known to facilitate tumor initiation,…  Read More »

Targeting the RB-pathway in sarcoma: Utility of CDK4/6 inhibitors

Sarcomas are a rare group of heterogeneous neoplasms arising from mesenchymal cells. Conventional cytotoxic chemotherapy and radiation therapy have failed to greatly improve disease-specific survival rates for most sarcomas with current 5-year survival rates for STS stagnant at approximately 50%. The field of sarcoma presents a clear need for new rational therapeutics, and discoveries in recent years regarding the molecular and genetic basis of sarcoma have posed new targets that deserve consideration. Alterations in the RB-pathway are one such example and have been demonstrated in various STS and OS. These alterations deactivate the RB-pathway and thus, lead to unabated cell…  Read More »

Epigenetic control of stem cell identity in rhabdoid sarcomas

Sarcomas characterized by the deficiency of SWI/SNF chromatin remodeling, including rhabdoid and synovial sarcomas, remain mostly lethal in spite of intensive chemotherapy, surgery and radiotherapy. Normal cells do not tolerate mutations of genes encoding SWI/SNF complexes, suggesting the existence of cooperating mechanisms that allow sarcoma cells to tolerate their deficiency and promote tumorigenesis. Rhabdoid sarcomas are known to be driven by abnormal regulation of gene expression, but its mechanisms remain elusive. Our recent work revealed an unanticipated requirement of an endogenous DNA transposase for the development of rhabdoid sarcomas. Its enforced expression is sufficient to induce malignant transformation of normal…  Read More »